Active Drugs: Effectiveness

Later studies found that the citrate anticoagulation used for platelet aggregation studies resulted in an overestimation of the inhibition by eptifibatide of platelet aggregation. Thus, it is unclear whether there is a differential effect of eptifibatide on the bleeding time. Active Drugs

Studies of C-eptifibatide administered as a single 135 g/kg IV bolus revealed mean peak plasma concentrations of 879 ± 251 ng/mL at 5 min, a mean distribution half-life of 5 ± 2.5 min, and a mean terminal elimination half-life of 1.1 ± 0.17 h. Of the approximately 73% of administered radioactivity recovered in 72 h, renal clearance accounted for 98% of the total recovered radioactivity, and for approximately 40% of total body clearance. Unmodified eptifibatide, deamidated eptifibatide, and more polar metabolites were all found in the urine, but only trace amounts of radioactivity were found in the breath and feces.

Since renal clearance is an important component of eptifibatide catabolism, patients with renal impairment can have prolonged inhibition of platelet function after receiving eptifibatide. This is of particular theoretical concern because patients with end-stage renal failure have platelet dysfunction Sildenafil Citrate Australia. The proper dose of eptifibatide in patients with modest-to-moderate renal insufficiency (creatinine level, 2 to 4 mg/dL) is uncertain. In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, patients with creatinine clearances of < 60 mL/min had increased major and minor bleeding rates compared to those patients with creatinine clearances of > 60 mL/min, and eptifibatide treatment increased both major and minor bleeding in both groups of patients.

Since the steady-state level of eptifibatide is approximately 1,900 ng/mL when using an infusion rate of 2 g/kg/min, the ratio of eptifibatide molecules to GPIIb/ IIIa molecules is > 50:1. Thus, platelet transfusions may not be able to reverse the effects of the drug, although in vitro data raise some hope in this regard. Treatment with eptifibatide prolongs the activated clotting time of patients who have received heparin, suggesting an inhibitory effect on thrombin generation.

In 21 patients undergoing elective PTCA or directional coronary atherectomy who were treated with aspirin, heparin (10,000 U bolus plus additional doses to maintain an activated clotting time of 300 to 350 s), and a bolus dose of 90 g/kg eptifibatide followed by infusion at a rate of 1 g/kg/min for 4 or 12 h, platelet aggregation was measured before infusion, 1 h after the bolus administration, at the end of the infusion, and 4 h after the end of the infusion. The extent of platelet aggregation in response to 20 mol/L ADP administration decreased from approximately 80% before eptifibatide administration to approximately 15% at both 1 h after the administration of the bolus dose and at the end of the infusion.

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Active Drugs: Effectiveness and Side Effects

In the Au-Assessing Ultegra (Gold) study, as with abciximab, there was a trend toward an association between lower levels of platelet function inhibition and the risk of major adverse cardiac events, but only a small number of patients was studied. In the Comparison of Measurements of Platelet Aggregation With Aggrastat, Reopro, and Eptifibatide (COMPARE) study, the effects of two dose regimens of tirofiban (infusion of 0.4 g/kg/min for 30 min and 0.1 g/kg/min thereafter, or a bolus dose of 10 g/kg followed by 0.15 g/kg/min infusion) were evaluated from 15 min to 12 h after starting therapy by aggregometry. At the early time points, the administration of tirofiban achieved less inhibition than that with abciximab or a single bolus of eptifibatide. At late time points, however, tirofiban administration achieved levels of inhibition that were comparable to those for eptifibatide and were greater than those achieved with abciximab.

In patients with renal insufficiency (creatinine clearance, < 30 mL/min), the plasma clearance of tirofiban is reduced and the plasma half-life is increased by more than threefold. The manufacturer recommends reducing both the bolus and infusion doses by 50%, but the pharmacokinetic basis for this recommendation has been challenged. In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, the 40 patients with creatinine clearance of  30 mL/min were found to have an increased risk of bleeding, and tirofiban treatment with Canadian Cialis further increased the risk.

Severe but reversible thrombocytopenia has been reported in a small percentage of patients treated with tirofiban, and an immunologic mechanism has been proposed, mediated by preformed antibodies to a conformation of the GPIIb/IIIa receptor induced by the binding of tirofiban to the receptor. No data are available on the safety of reinfusing tirofiban, but high-titer antibodies have been identified in patients who developed thrombocytopenia after repeat administration.

Eptifibatide (Integrilin; Millennium Pharmaceuticals; Cambridge, MA) is a synthetic disulfide-linked cyclic heptapeptide. It is patterned after the Lys-Gly-Asp sequence found in the snake venom disintegrin, obtained from Sistrurus m. barbouri (barbourin), and it has high specificity, but not absolute specificity, for inhibition of GPIIb/IIIa compared with inhibition of the aVp3 vitronectin receptor. Preliminary reports have suggested that eptifibatide produced less prolongation of the bleeding time than other GPIIb/IIIa inhibitors at doses producing comparable inhibition of platelet aggregation.